The association of human emphysema with deficiency of the serum protease inhibitor alpha-1-antitrypsin (AAT) has stimulated efforts to discover the cause of AAT deficiency as a first step to developing prophylaxis and therapy for the illness and disability it causes. Existing evidence implicates the liver as a site of AAT synthesis rather than simple storage but only one study, using embryonic and fetal liver, has shown synthesis of AAT that was identified by specific antibody. Efforts to understand the mechanism of AAT deficiency would be aided greatly by a system capable of human AAT synthesis and secretion in vitro which would permit manipulations and control of experimental conditions that are not possible in human subjects. The objectives of the proposed research are: (1) to identify the organ sites of AAT synthesis and secretion, (2) to isolate cultured cells that synthesize and secrete human AAT in vitro, and (3) to use these cells to study the action of genes producing AAT deficiency. To detect AAT synthesis, mouse and human autopsy liver and other tissues will be incubated with medium containing 14C-leucine, and concentrated medium will be subjected to crossed antigen-antibody electrophoresis with carrier serum, followed by radioautography.